ALS is a devastating disease causing progressive motor neuron degeneration and death. Most ALS patients develop severe respiratory insufficiency and, ultimately, die from ventilatory failure. Despite its fundamental mportance, respiratory function has seldom been studied in any ALS model. In this revised application, we focus attention on respiratory motor function in a rodent model of familial ALS, the transgenic rat over- expressing mutated superoxide dismutase-1 (SOD1G93A rat). The fundamental hypothesis guiding this proposal is that compensatory spinal neuroplasticity offsets severe motor neuron degeneration, preserving the ability to breathe until late in disease progression. We propose to investigate mechanisms of compensatory spinal plasticity in SOD1G93A rats, and to determine if further plasticity can be induced with ghronic treatments that enhance respiratory plasticity, such as intermittent exposures to low oxygen (hypoxia). We also propose to investigate the contributions of key trophic factors postulated to play key roles in respiratory plasticity or ALS pathogenesis: brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). To achieve our primary goal, four specific hypotheses will be tested: 1) SOD1G93A rats utilize compensatory spinal neuroplasticity to preserve ventilatory function despite severe inspiratory motor neuron cell death; 2) daily intermittent hypoxia enhances respiratory plasticity and actually delays disease progression; 3) serotonin-dependent BDNF regulation underlies compensatory respiratory plasticity during ALS; and 4) VEGF improves respiratory motor output and motor neuron survival. Our perspective is unique, focusing on compensatory mechanisms that offset progressive motor neuron degeneration, thereby preserving function in a critical, homeostatic motor system. The utilization of diverse and highly innovative experimental approaches (e.g., RNA interference in vivo; and transplantation of neural progenitor cells secreting trophic factors), the extensive experience of the laboratory with all aspects of this proposal, and exciting preliminary data increase the likelihood that the proposed experiments will significantly advance our understanding of ALS. Collectively, these aims will provide unique insights concerning the progression of familial ALS (and other forms by inference), and may provide the rationale for novel therapeutic strategies for a neurodegenerative disease with no known cure.